Rosai-Dorfman Disease or Sinus Histiocytosis
with Massive Lymphadenopathy (SHML) is a rare benign disease of unknown etiology,
which presents with cervical lymphadenopathy. It is usually seen in younger
patients. The extranodal form affect various regions of the head and neck, and
is more common in patients with immune abnormalities. It is a self-limited and
seldom life-threatening disease, rendering therapy unnecessary in most cases.
For those who require therapy because of persistent or worsening symptoms, treatments
modalities include surgery, chemotherapy, radiotherapy and steroids. The authors
describe one case of a 43-year-old man with bilateral cervical masses, nasal
obstruction, fever, weight loss and decreased vision with 6 months duration.
As his social history was positive for tobacco and alcohol use, the initial
diagnosis was a possible rhinopharyngeal malignant tumor. Medical investigation
established the diagnosis of SHML. After therapy, the 6-month follow-up evidenced
the patient's clinical improvement, although cervical masses persisted. The
clinical presentation, histological features, pathogenesis and treatment of
this case are discussed.

Keywords: cervical lymphadenopathy, rosai-dorfman disease.

INTRODUCTION

Sinus histiocytosis with massive lymphadenopathy
(SHML) was described in 1969 by Rosai and Dorfman in a report of four cases;1
the same authors characterized this disease in greater detail in 1972.2
It is a rare, benign lymphoproliferative condition presenting with painless
cervical lymphadenopathy, fever, leukocytosis with neutrophilia, increased hemosedimentation
rate and polyclonal hypergammaglobulinemia.3,4 Other lymph node groups
may be involved; 30-40% of cases have extranodal disease.1-3,6 This
condition generally affects children and young adults;5 the mean age at presentation
is 19.7 years.4 It affects equally white and black people, and is
less frequent in Asians. The disease is found worldwide and appears to affect
males more than females, in a 1.4:1.0 ratio.6 Its etiology remains
uncertain. Possible causes include altered immune responses and infections by
agents such as varicella-zooster and other herpetic viruses, Epstein-Barr and
cytomegalovirus, Brucella and Klebisiela.4 Treatment is controversial.
Other modalities have been attempted, such as surgery, antibiotics, radiotherapy,
chemotherapy and steroids, sometime in combination; none has provided consistent
results. We present a case that was diagnosed and treated in our clinical unit,
and make a brief review of the literature.

CASE REPORT

GCO, a male patient aged 43 years, sought the
otorhinolaryngology and head & neck surgery unit presenting bilateral neck
masses, nasal block, significant weight loss, malaise, evening fever and loss
of vision. These symptoms had progressed during the past 6 months. There was
no nasal bleeding, odynophagia or dysphonia.

The physical examination showed bilateral neck
nodules of different sizes, as shown in figure 2. The nodules
were coalescent, adhered to deeper planes and painless. There were no other
findings.

Fine needle aspiration biopsy (FNAB) was done
of a nodule. Other exams were nasal endoscopy, computed tomography (CT) of the
neck, a complete blood count, hepatic function tests, screening for autoimmune
diseases, VDRL and HIV serology, and testing for toxoplasmosis. These exams
revealed leukocytosis and neutrophilia. Anti-HIV, VDRL and serology for toxoplasmosis
were negative. The FNAB was non-conclusive; there were lymphocytes, occasional
neutrophils and no neoplastic cells.

Nasal endoscopy showed a large lobulated tumor
in the cavum (Figure 1), which occluded most of the choanae.
CT of the neck showed an expanding solid lesion in the retropharyngeal and parapharyngeal
space, projecting into the nasopharyngeal lumen. There was also cervical and
submandibular lymph node enlargement.

The tumor was biopsied under endoscopic view.
Histology showed a diffuse submucosal infiltration by plasma cells containing
lymphocytes within their cytoplasm.

While these exams were done, the patient worsened
progressively, presenting bilateral axillary and inguinal lymph node enlargement,
diffuse facial skin lesions and further loss of vision.

The 6-month follow-up showed that the patient
improved significantly, but the neck masses regressed only slightly.

DISCUSSION

SHML is a rare cause of lymph node enlargement
in children and young adults; 80% of cases occur under the age 20 years. Many
cases of extranodal involvement have been described since 1969. Apparently,
there is no relation between lymph node and extranodal disease; they may even
occur separately.2

The etiology is uncertain, although agents such
as the Epstein-Barr or herpes viruses are important in the pathogenesis.3

The onset of SHML is typically insidiously; the
active phase is prolonged, there may be spontaneous remission and subsequent
relapses.3 Factors that determine recurrences and is frequency are
not well understood. Deaths have been reported due to infiltration of vital
organs, such as the liver.4 The neck lymph nodes are the most frequently
involved, followed by inguinal, axillary and mediastinal lymph nodes.5
The most common extranodal sites are the skin, the upper respiratory tract and
bones. Head and neck involvement - about 22% of extranodal disease4,5
- include involvement of the nasal cavity, the paranasal sinuses, the nasopharynx,
submandibular glands, the parotid, the larynx, the temporal bone, the intratemporal
fossa, the pterygoid fossa, the meninges and the orbit.5 The skin
is commonly affected; half of these patients have another associated extranodal
site. Orbit and ocular glove involvement have been reported, usually as a retroorbitary
mass and proptosis.6

The differential diagnosis of extranodal SHML
may be a challenge, and is based on the clinical and histological examination.
Histology shows typical features, such as diffuse lymphoplasmatic infiltration,
Russel bodies, foamy histiocytes and histiocytes with phagocytosed lymphocytes
within the cytoplasm (emperipolesis). Immunohistochemical features include positive
S-100, alpha-antichymotrypsin and CD1a and CD68 antigens.4,5 Imaging
(CT and magnetic resonance imaging) may be used to assess disease extension.
If there is cervical lymph node enlargement, FNAB or lymph node biopsies may
be useful for the diagnosis.3

In the case above, FNAB and a cervical biopsy
were done to exclude the possibility of neck metastases from local malignancies.
Nasal endoscopy was extremely useful in detecting the primary lesion, and CT
of the neck demonstrated the disease extension.

The differential diagnosis is made with lymphoreticular
malignancies such as lymphomas, Hodgkin's disease, malignant histiocytosis and
monocytic leukemia, all of which have similar histopathological features. Atypias
in cytology and the aggressive clinical course establish the diagnosis in most
cases. Other histiocytoses, such as rhinoscleromas, Wegener's granulomatosis,
may also be included in the differential diagnosis.6 Serology for HIV, toxoplasmosis
and syphilis was done since these conditions are not rare in our context. Extranodal
manifestations in the head and neck are significantly more common in SHML patients
with immunological abnormalities.4,5 SHML has been described in HIV-infected
patients. An altered immune system and liver, kidney or lower airway involvement
are considered as factors that worsen the prognosis.3

Immunohistochemical exams were not done in our
patient; the public health system (Sistema Unico de Saude) did not authorize
these tests. The diagnosis, therefore, was confirmed histologically.

The patient next underwent radiological and other
image diagnostic tests (a chest X-ray, abdominal ultrasound and CT of the head)
to investigate further extranodal involvement. The rhinopharyngeal lesion and
diffuse skin lesions on the face were considered extranodal involvement of this
disease. We did not correlate poor vision with the disease in this patient.

There is no ideal protocol for the treatment
of SHML; it is an uncommon, self-limited disease that frequently requires no
therapy. Treatment is only necessary when lymph node or extranodal tissue enlargement
causes significant symptoms, such as airway obstruction or compression of vital
organs. Pulsone at al. reviewed 80 cases published between 1969 and 2000; 50%
of these cases required no treatment, of which 82% had full remission.4
The role of surgery is mostly for biopsies and to relieve obstruction.3
Local recurrence is frequent following surgical resection. The role of radiotherapy
is not well understood; some reports have described full resolution with this
treatment, while others have shown no response.2 Steroids often resolve
fever and reduce lymph node size. Chemotherapy has yielded controversial results.
A possible efficacy of methotrexate and 6-mercaptopurine requires further investigation.
Other reports have suggested using alpha-interferon, although its side effects
have limited its use.4

We treated our patient with corticosteroids,
to which he responded well. The patient was sent to an oncology unit for chemotherapy,
which was eventually not done. Surgery was not required, given the benign nature
of the condition.

FINAL COMMENTS

SHML is rare, requiring knowledge of its main
clinical manifestations for a correct diagnosis. The differential diagnosis
includes a variety of diseases. The diagnosis of SHML is made by histopathology;
other exams may be useful. Therapy and when to begin treatment remains controversial.
Follow-up is necessary to avoid relapses.